We have started to characterize and develop pedigrees with high susceptibility to diabetes mellitus. Thirty one nuclear or extended families and 20 sibs have been characterized so far. Affected and unaffected family members were recruited to Rockefeller University Hospital through collaborations with medical centers and private physicians from the New York area and from advertisements in newspapers and the Internet. A metabolic workup including fasting glucose, oral glucose tolerance test, insulin, C-peptide, glycosylated hemoglobin, lipid profile as well as a detailed medical history were performed and documented. DNA was extracted (average of 500 micrograms/patient) from all individuals studied. In addition, 3 ml of serum was frozen and stored. We have started to screen diabetic patients for mutations in hepatocyte nuclear factor 4-alpha and 1-alpha (mutations in HNF1-alpha were recently shown to be responsible for MODY3) in order to determine the prevalences of these genetic defects in various populations. Various mutations in the HNF1-alpha and variations in the HNF4-alpha gene have so far been identified and are currently under investigation.